The determinants of quality in procedural rural medical care.
A substantial proportion of health services for rural Australians is provided in rural health facilities by rurally based generalist health professionals. These services include procedural care within smaller rural hospitals, where teams of health professionals--medical practitioners, nurses and other support staff--work in teams to deliver a range of procedural services, both elective and urgent, that reduce the need for rural people to travel to major centres. Recent debate over the training of rural medical practitioners has focused on whether or not they need to provide procedural services, because current health service management policy appears to support the rationalisation and centralisation of service delivery in larger centres to contain costs and ensure high quality. Hence there is an assumption, without much evidence, that the quality of care in rural hospitals is lower than that provided in larger urban hospitals, although there is little agreement on just what aspects of care should be measured to indicate its quality. This article reports an exploration of multiple perspectives on what constitutes quality of care in rural procedural medical practice, as part of a broader study of the quality of care of a series of real clinical cases. During the collection of a series of 91 individual patient cases involving anaesthetic, obstetric or surgical procedures conducted in small rural hospitals, interviews were conducted with several participants in each case: the rural doctors; rural nurses; the rural patients; and family members of those patients. In addition to issues pertaining to each case, interviews explored the perspectives of individuals in each group on the broader question of what constitutes quality of care in a general sense. Their comments were subjected to qualitative thematic analysis using Atlas.ti software (Muhr T, ATLAS.ti Scientific Software Development; Berlin, Germany). In order to consider how to measure rural health care, the thematic comments were then applied to a Donabedian structure/process/outcome model. The different groups produced different views on what might determine the quality of health care in rural hospitals. The health professionals tended to focus on technical aspects of care, although the doctors and nurses had some different emphases, while the patients and their families were more concerned with access, interpersonal communication, convenience and cost. These themes appeared to be consistent with previous literature from general healthcare settings. A list of indicators is suggested for measuring the quality of rural health care. This study has improved understanding of the differing views held by rural health professionals and rural patients in thinking about the quality of care provided in rural hospitals. Consideration of the quality of procedural rural medical care should include the needs and expectations of those living and working in a smaller, more familiar environment. This has implications for health planners, and suggests that there is a continuing need for rural health professionals to be trained to provide procedural medical services in rural hospitals, and for rural hospitals to be maintained at a standard necessary to support quality service provision.


Relationship between glycated hemoglobin, Intensive Care Unit admission blood sugar and glucose control with ICU mortality in critically ill patients.
The association between hyperglycemia and mortality is believed to be influenced by the presence of diabetes mellitus (DM). In this study, we evaluated the effect of preexisting hyperglycemia on the association between acute blood glucose management and mortality in critically ill patients. The primary objective of the study was the relationship between HbA1c and mortality in critically ill patients. Secondary objectives of the study were relationship between Intensive Care Unit (ICU) admission blood glucose and glucose control during ICU stay with mortality in critically ill patients. Five hundred patients admitted to two ICUs were enrolled. Blood sugar and hemoglobin A1c (HbA1c) concentrations on ICU admission were measured. Age, sex, history of DM, comorbidities, Acute Physiology and Chronic Health Evaluation II score, sequential organ failure assessment score, hypoglycemic episodes, drug history, mortality, and development of acute kidney injury and liver failure were noted for all patients. Without considering the history of diabetes, nonsurvivors had significantly higher HbA1c values compared to survivors (7.25 ± 1.87 vs. 6.05 ± 1.22, respectively, P < 0.001). Blood glucose levels in ICU admission showed a significant correlation with risk of death (P < 0.006, confidence interval [CI]: 1.004-1.02, relative risk [RR]: 1.01). Logistic regression analysis revealed that HbA1c increased the risk of death; with each increase in HbA1c level, the risk of death doubled. However, this relationship was not statistically significant (P: 0.161, CI: 0.933-1.58, RR: 1.2). Acute hyperglycemia significantly affects mortality in the critically ill patients; this relation is also influenced by chronic hyperglycemia.


Predicting Recovery Patterns After Sport-Related Concussion.
Clinicians sometimes treat concussed individuals who have amnesia, loss of consciousness (LOC), a concussion history, or certain symptom types more conservatively, but it is unclear whether recovery patterns differ in individuals with these characteristics. To determine whether (1) amnesia, LOC, and concussion history influence the acute recovery of symptoms, cognition, and balance; and (2) cognition and balance are influenced by acute symptom type. Cohort study. Seven sports at 26 colleges and 210 high schools. A total of 8905 collegiate (n = 1392) and high school (n = 7513) athletes. The Graded Symptom Checklist, Standardized Assessment of Concussion, and Balance Error Scoring System were administered to all athletes during the preseason. To allow us to track recovery patterns, athletes diagnosed with a concussion (n = 375) repeated these assessments immediately after the injury, 3 hours postinjury, 1 day postinjury, and at 2, 3, 5, 7, and 90 days after injury. Athletes who experienced amnesia had markedly greater deficits in and a slower recovery trajectory on measures of symptoms, cognition, and balance. Athletes with 2 or more prior concussions demonstrated poorer balance than those with no previous history. Otherwise, LOC and concussion history largely did not affect symptoms, cognition, or balance. Greater deficits in balance scores were observed in athletes with all symptom types. Regardless of these characteristics, most athletes recovered within 7 to 10 days. Athletes who experienced amnesia had more symptoms and greater deficits in cognition and balance. Symptoms and cognitive or balance deficits were not consistently associated with LOC or concussion history. Acute symptoms had a strong influence on balance scores and, to a lesser extent, on cognition. However, we found no evidence to support more cautious return-to-play decisions for athletes with these characteristics, as group recovery occurred within normal timelines. Our study supports current clinical practice: recommending that athletes be withheld from activity until they are asymptomatic, followed by a graduated return-to-play progression.


Analysis of quantitative [I-123] mIBG SPECT/CT in a phantom and in patients with neuroblastoma.
To determine the accuracy of quantitative SPECT, intersystem and interpatient standardized uptake value (SUV) calculation consistency for a manufacturer-independent quantitative SPECT/CT reconstruction algorithm, and the range of SUVs of normal and neoplastic tissue. A NEMA body phantom with 6 spheres (ranging 10-37 mm) was filled with a known activity-to-volume ratio and used to determine the contrast recovery coefficient (CRC) for each visible sphere, and the measured SUV accuracy of those spheres and background water solution. One hundred eleven 123I-metaiodobenzylguanidine ([I-123] mIBG) SPECT/CT examinations from 43 patients were reconstructed using SUV SPECT® (HERMES Medical Solutions Inc.); 42 examinations were acquired using a GE Infinia Hawkeye 4 SPECT/CT, and 69 were acquired on a Siemens Symbia Intevo SPECT/CT. Inter scanner SUV analysis of 9 regions of normal [I-123] mIBG tissue uptake was conducted. Intrapatient mean SUV variability was calculated by measuring normal liver uptake within patients scanned on both cameras. The intensity of uptake by neoplastic tissue in the images was quantified using maximum SUV and, if present, compared over time. The phantom results of the visible spheres and background resulted in accuracy calculations better than 5-10% with CRC correction. Interscanner SUV variability showed no statistical difference (average p value 0.559; range 0.066-1.0) among the 9 normal tissues analyzed. Intrapatient liver mean SUV varied ≤ 16% as calculated for 28 patients (87 examinations) studied on both scanners. In one patient, a thoracic tumor evaluated over 10 time points (18 months) underwent a 74% (3.1/12.0) reduction in maximum SUV with treatment. The results demonstrate quantitative accuracy to better than 10%, and both consistent SUV calculation between 2 different SPECT/CT scanners for 9 tissues, and low intrapatient measurement variability for quantitative SPECT/CT analysis in a pediatric population with neuroblastoma. Quantitative SPECT/CT offers the opportunity for objective analysis of tumor response using [I-123] mIBG by normalizing the uptake to injected dose and patient weight, as is done for PET.


Significance of the interferon (IFN) in the therapy.
Interferons belong to the group of the regulatory glycoproteins, of low molecular mass. They are the products of infected cell-genome, but not virus, as a consequence of the cause answer by different inductors. Human IFN are divided on the sequence of amino-acids into three groups: Alpha, Beta and Gamma interferons. Recently are discovered new types of IFNs: Omega and Tau, but bigger than alpha molecules. Also, has been performed the division into two types: I and II. Besides the antiviral and antiproliferative effects, they have also the effect in the treatment of malignant diseases, and act protectively against the radiation.


Effects of pomegranate juice on blood pressure: A systematic review and meta-analysis of randomized controlled trials.
Punica granatum L. (Pomegranate) has been claimed to provide several health benefits. Pomegranate juice is a polyphenol-rich fruit juice with high antioxidant capacity. Several studies suggested that pomegranate juice can exert antiatherogenic, antioxidant, antihypertensive, and anti-inflammatory effects. Nevertheless, the potential cardioprotective benefits of pomegranate juice deserve further clinical investigation. To systematically review and meta-analyze available evidence from randomized placebo-controlled trials (RCTs) investigating the effects of pomegranate juice consumption and blood pressure (BP). A comprehensive literature search in Medline and Scopus was carried out to identify eligible RCTs. A meta-analysis of eligible studies was performed using a random-effects model. Quality assessment, sensitivity analysisand publication bias evaluations were conducted using standard methods. Quantitative data synthesis from 8 RCTs showed significant reductions in both systolic [weighed mean difference (WMD): -4.96mmHg, 95% CI: -7.67 to -2.25, p<0.001) and diastolic BP (WMD: -2.01mmHg, 95% CI: -3.71 to -0.31, p=0.021) after pomegranate juice consumption. Effects on SBP remained stable to sensitivity analyses. Pomegranate juice reduced SBP regardless of the duration (>12 wks: WMD=-4.36mmHg, 95% CI: -7.89 to -0.82, p=0.016) and <12 wks: WMD=-5.83 mmHg, 95% CI: -10.05 to -1.61, p=0.007) and dose consumed (>240cc: WMD=-3.62mmHg, 95% CI: -6.62 to -0.63, p=0.018) and <240cc: WMD=-11.01mmHg, 95% CI: -17.38 to -4.65, p=0.001, pomegranate juice per day) whereas doses >240cc provided a borderline significant effect in reducing DBP. The present meta-analysis suggests consistent benefits of pomegranate juice consumption on BP. This evidence suggests it may be prudent to include this fruit juice in a heart-healthy diet.


Occupational allergy in laboratory workers caused by the African migratory grasshopper Locusta migratoria.
Recent reports of fatal asthma cases associated with swarms of locusts affecting African countries have highlighted the importance of this insect in causing asthma morbidity and mortality. However, only limited information is available about the allergic health outcomes such as asthma and its determinants in exposed individuals. In this study, workers exposed to the African migratory locust Locusta migratoria were evaluated for allergic health outcomes as well as the nature of the offending allergens. Ten scientists and technicians exposed to locusts in a laboratory were investigated for locust-related allergy using questionnaires and immunological tests. The presence of allergy was determined by quantification of specific IgE and IgG to L. migratoria using the UniCAP system and via skin-prick testing (SPT). The allergens were characterized by Western blot and ImmunoCAP inhibition assays. Six of the 10 workers experienced symptoms ranging from urticaria and rhinoconjuctivitis to asthma. Seven individuals demonstrated sensitivity on SPT and five had specific IgE antibodies to L. migratoria. Significant cross-reactivity was demonstrated for allergens in the locust faeces, body and wings but not to cockroach allergens. Novel allergens with molecular weights of approximately 70 kDa were identified in locust wings, which are distinctly different from other known allergen sources from locusts. Exposure to L. migratoria allergens is a potential sensitizer in exposed individuals. Raised levels of locust-specific IgE can be readily quantified. The wings of this insect species have been identified as a novel allergen source.


Metal-organic frameworks for luminescence thermometry.
Metal-organic frameworks (MOFs) hold great promise for developing various types of luminescent sensors due to their remarkable structural diversity and tunable luminescence properties. In the last few years, utilizing luminescent MOFs to explore temperature sensing has gained intense attention. In this feature article, after the general description of luminescence thermometry, we have summarized the recent progress made in luminescent MOF thermometers, with particular emphasis on the dual-emitting MOFs that effectively illustrate the self-referencing temperature measurement based on the intensity ratios of two separate transitions.


The physiologically modulated electrode potentials at the depth electrode-brain interface in humans.
To study the modulated electrical potential specifically related to the electrode-brain interface (EBI) in deep brain stimulation (DBS) under physiological condition, we quantitatively identified the physiologically modulated electrode potentials by decomposing the local field potentials (LFPs) recorded from 11 patients (18 electrodes in four different brain regions) who underwent DBS, and correlated them with simultaneously recorded physiological signals of blood pressure (BP) and respiration. Results showed that electrode potentials were modulated by BP and respiration and could be detected as a specific component of the compound LFP signals with a mean (+/-S.D.) amplitude of 6.9+/-1.7 microV. The detection rate and amplitude of the modulated electrode potentials were independent from brain regions and neurological disorders. The current approach can be used to study the changes in properties of the EBI under physiological condition and to investigate the effects of the EBI on the 'crossing' current of either the neural signals to be recorded or the electrical pulses for neurostimulation.


Putting the C back into the ABCs: a multi-year, multi-region investigation of condom use by Ugandan youths 2003-2010.
A major strategy for preventing transmission of HIV and other STIs is the consistent use of condoms during sexual intercourse. Condom use among youths is particularly important to reduce the number of new cases and the national prevalence. Condom use has been often promoted by the Uganda National AIDS Commission. Although a number of studies have established an association between condom use at one's sexual debut and future condom use, few studies have explored this association over time, and whether the results are generalizable across multiple locations. This multi time point, multi district study assesses the relationship between sexual debut and condom use and consistent use of condoms thereafter. Uganda has used Lot Quality Assurance Sampling surveys since 2003 to monitor district level HIV programs and improve access to HIV health services. This study includes 4518 sexually active youths interviewed at five time points (2003-2010) in up to 23 districts located across Uganda. Using logistic regression, we measured the association of condom use at first sexual intercourse on recent condom usage, controlling for several factors including: age, sex, education, marital status, age at first intercourse, geographical location, and survey year. The odds of condom use at last intercourse, using a condom at last intercourse with a non-regular partner, and consistently using a condom are, respectively, 9.63 (95%WaldCI = 8.03-11.56), 3.48 (95%WaldCI = 2.27-5.33), and 11.12 (95%WaldCI = 8.95-13.81) times more likely for those individuals using condoms during their sexual debut. These values did not decrease by more than 20% when controlling for potential confounders. The results suggest that HIV prevention programs should encourage condom use among youth during sexual debut. Success with this outcome may have a lasting influence on preventing HIV and other STIs later in life.


In silico identification of plant miRNAs in mammalian breast milk exosomes--a small step forward?
MicroRNAs (miRNAs) are a class of small RNA molecules that regulate gene expression by inhibiting the protein translation or targeting the mRNA cleavage. They play many important roles in living organism cells; however, the knowledge on miRNAs functions has become more extensive upon their identification in biological fluids and recent reports on plant-origin miRNAs abundance in human plasma and serum. Considering these findings, we performed a rigorous bioinformatics analysis of publicly available, raw data from high-throughput sequencing studies on miRNAs composition in human and porcine breast milk exosomes to identify the fraction of food-derived miRNAs. Several processing and filtering steps were applied to increase the accuracy, and to avoid false positives. Through aforementioned analysis, 35 and 17 miRNA species, belonging to 25 and 11 MIR families, were identified, respectively. In the human samples the highest abundance levels yielded the ath-miR166a, pab-miR951, ptc-miR472a and bdi-miR168, while in the porcine breast milk exosomes, the zma-miR168a, zma-miR156a and ath-miR166a have been identified in the largest amounts. The consensus prediction and annotation of potential human targets for select plant miRNAs suggest that the aforementioned molecules may interact with mRNAs coding several transcription factors, protein receptors, transporters and immune-related proteins, thus potentially influencing human organism. Taken together, the presented analysis shows proof of abundant plant miRNAs in mammal breast milk exosomes, pointing at the same time to the new possibilities arising from this discovery.


Association Between Population Density and Genetic Risk for Schizophrenia.
Urban life has been proposed as an environmental risk factor accounting for the increased prevalence of schizophrenia in urban areas. An alternative hypothesis is that individuals with increased genetic risk tend to live in urban/dense areas. To assess whether adults with higher genetic risk for schizophrenia have an increased probability to live in more populated areas than those with lower risk. Four large, cross-sectional samples of genotyped individuals of European ancestry older than 18 years with known addresses in Australia, the United Kingdom, and the Netherlands were included in the analysis. Data were based on the postcode of residence at the time of last contact with the participants. Community-based samples who took part in studies conducted by the Queensland Institute for Medical Research Berghofer Medical Research Institute (QIMR), UK Biobank (UKB), Netherlands Twin Register (NTR), or QSkin Sun and Health Study (QSKIN) were included. Genome-wide association analysis and mendelian randomization (MR) were included. The study was conducted between 2016 and 2018. Polygenic risk scores for schizophrenia derived from genetic data (genetic risk is independently measured from the occurrence of the disease). Socioeconomic status of the area was included as a moderator in some of the models. Population density of the place of residence of the participants determined from census data. Remoteness and socioeconomic status of the area were also tested. The QIMR participants (15 544; 10 197 [65.6%] women; mean [SD] age, 54.4 [13.2] years) living in more densely populated areas (people per square kilometer) had a higher genetic loading for schizophrenia (r2 = 0.12%; P = 5.69 × 10-5), a result that was replicated across all 3 other cohorts (UKB: 345 246; 187 469 [54.3%] women; age, 65.7 [8.0] years; NTR: 11 212; 6727 [60.0%] women; age, 48.6 [17.5] years; and QSKIN: 15 726; 8602 [54.7%] women; age, 57.0 [7.9] years). This genetic association could account for 1.7% (95% CI, 0.8%-3.2%) of the schizophrenia risk. Estimates from MR analyses performed in the UKB sample were significant (b = 0.049; P = 3.7 × 10-7 using GSMR), suggesting that the genetic liability to schizophrenia may have a causal association with the tendency to live in urbanized locations. The results of this study appear to support the hypothesis that individuals with increased genetic risk tend to live in urban/dense areas and suggest the need to refine the social stress model for schizophrenia by including genetics as well as possible gene-environment interactions.


Nanobody Engineering: Toward Next Generation Immunotherapies and Immunoimaging of Cancer.
In the last decade, cancer immunotherapies have produced impressive therapeutic results. However, the potency of immunotherapy is tightly linked to immune cell infiltration within the tumor and varies from patient to patient. Thus, it is becoming increasingly important to monitor and modulate the tumor immune infiltrate for an efficient diagnosis and therapy. Various bispecific approaches are being developed to favor immune cell infiltration through specific tumor targeting. The discovery of antibodies devoid of light chains in camelids has spurred the development of single domain antibodies (also called VHH or nanobody), allowing for an increased diversity of multispecific and/or multivalent formats of relatively small sizes endowed with high tissue penetration. The small size of nanobodies is also an asset leading to high contrasts for non-invasive imaging. The approval of the first therapeutic nanobody directed against the von Willebrand factor for the treatment of acquired thrombotic thrombocypenic purpura (Caplacizumab, Ablynx), is expected to bolster the rise of these innovative molecules. In this review, we discuss the latest advances in the development of nanobodies and nanobody-derived molecules for use in cancer immunotherapy and immunoimaging.


Prostasin, a potential serum marker for ovarian cancer: identification through microarray technology.
Screening biomarkers for ovarian cancer are needed because of its late stage at diagnosis and poor survival. We used microarray technology to identify overexpressed genes for secretory proteins as potential serum biomarkers and selected prostasin, a serine protease normally secreted by the prostate gland, for further study. RNA was isolated and pooled from three ovarian cancer cell lines and from three normal human ovarian surface epithelial (HOSE) cell lines. Complementary DNA generated from these pools was hybridized to a microarray slide, and genes overexpressed in the cancer cells were identified. Real-time quantitative polymerase chain reaction was used to examine prostasin gene expression in ovarian cancer and HOSE cell lines. Anti-prostasin antibodies were used to examine prostasin expression and to measure serum prostasin by an enzyme-linked immunosorbent assay in 64 case patients with ovarian cancer and in 137 control subjects. Previously determined levels of CA 125, an ovarian cancer marker, were available from about 70% of all subjects. All statistical tests were two-sided. Prostasin was detected by immunostaining more strongly in cancerous ovarian epithelial cells and stroma than in normal ovarian tissue. The mean level of serum prostasin was 13.7 microg/mL (95% confidence interval [CI] = 10.5 to 16.9 microg/mL) in 64 case patients with ovarian cancer and 7.5 microg/mL (95% CI = 6.6 to 8.3 microg/mL) in 137 control subjects (P<.001, after adjustment for the subject's age, year of collection, and specimen quality). In 14 of 16 case patients with both preoperative and postoperative serum samples, postoperative prostasin levels were statistically significantly lower than preoperative levels (P =.004). In 37 case patients with nonmucinous ovarian cancer and in 100 control subjects for whom levels of CA 125 and prostasin were available, the combination of markers gave a sensitivity of 92% (95% CI = 78.1% to 98.3%) and a specificity of 94% (95% CI = 87.4% to 97.7%) for detecting ovarian cancer. Prostasin is overexpressed in epithelial ovarian cancer and should be investigated further as a screening or tumor marker, alone and in combination with CA 125.


Nutrition myths and healthy dietary advice in clinical practice.
Healthy dietary intake is important for the maintenance of general health and wellness, the prevention of chronic illness, the optimization of life expectancy, and the clinical management of virtually all disease states. Dietary myths (i.e., concepts about nutrition that are poorly supported or contradicted by scientific evidence) may stand in the way of healthy dietary intake. Dietary myths exist about micronutrients, macronutrients, non-nutrients, and food energy. Representative myths of each type include that patients need to focus on consuming enough calcium to ensure bone health, dietary fat leads to obesity and is detrimental to vascular health, all fiber (whether naturally occurring or artificially added) is beneficial, and food calories translate to pounds of body weight through a linear relationship and simple arithmetic. A common theme for dietary myths is a reductionist view of diet that emphasizes selected food constituents as opposed to whole foods. Healthy dietary advice takes a more holistic view; consistent evidence supports recommendations to limit the consumption of ultraprocessed foods and to eat whole or minimally processed foods, generally in a form that is as close to what occurs in nature as possible. Family physicians can help dispel myths for patients and give sound nutritional advice by focusing on actual foods and broader dietary patterns.


Capturing and profiling adult hair follicle stem cells.
The hair follicle bulge possesses putative epithelial stem cells. Characterization of these cells has been hampered by the inability to target bulge cells genetically. Here, we use a Keratin1-15 (Krt1-15, also known as K15) promoter to target mouse bulge cells with an inducible Cre recombinase construct or with the gene encoding enhanced green fluorescent protein (EGFP), which allow for lineage analysis and for isolation of the cells. We show that bulge cells in adult mice generate all epithelial cell types within the intact follicle and hair during normal hair follicle cycling. After isolation, adult Krt1-15-EGFP-positive cells reconstituted all components of the cutaneous epithelium and had a higher proliferative potential than Krt1-15-EGFP-negative cells. Genetic profiling of hair follicle stem cells revealed several known and unknown receptors and signaling pathways important for maintaining the stem cell phenotype. Ultimately, these findings provide potential targets for the treatment of hair loss and other disorders of skin and hair.


Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).
High-definition transcranial direct current stimulation (HD-tDCS) has recently been developed as a noninvasive brain stimulation approach that increases the accuracy of current delivery to the brain by using arrays of smaller "high-definition" electrodes, instead of the larger pad-electrodes of conventional tDCS. Targeting is achieved by energizing electrodes placed in predetermined configurations. One of these is the 4x1-ring configuration. In this approach, a center ring electrode (anode or cathode) overlying the target cortical region is surrounded by four return electrodes, which help circumscribe the area of stimulation. Delivery of 4x1-ring HD-tDCS is capable of inducing significant neurophysiological and clinical effects in both healthy subjects and patients. Furthermore, its tolerability is supported by studies using intensities as high as 2.0 milliamperes for up to twenty minutes. Even though 4x1 HD-tDCS is simple to perform, correct electrode positioning is important in order to accurately stimulate target cortical regions and exert its neuromodulatory effects. The use of electrodes and hardware that have specifically been tested for HD-tDCS is critical for safety and tolerability. Given that most published studies on 4x1 HD-tDCS have targeted the primary motor cortex (M1), particularly for pain-related outcomes, the purpose of this article is to systematically describe its use for M1 stimulation, as well as the considerations to be taken for safe and effective stimulation. However, the methods outlined here can be adapted for other HD-tDCS configurations and cortical targets.


The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth disease type 4B (CMT4B) is a severe, demyelinating peripheral neuropathy characterized by distinctive, focally folded myelin sheaths. CMT4B is caused by recessively inherited mutations in either myotubularin-related 2 (MTMR2) or MTMR13 (also called SET-binding factor 2). MTMR2 encodes a member of the myotubularin family of phosphoinositide-3-phosphatases, which dephosphorylate phosphatidylinositol 3-phosphate (PI(3)P) and bisphosphate PI(3,5)P2. MTMR13 encodes a large, uncharacterized member of the myotubularin family. The MTMR13 phosphatase domain is catalytically inactive because the essential Cys and Arg residues are absent. Given the genetic association of both MTMR2 and MTMR13 with CMT4B, we investigated the biochemical relationship between these two proteins. We found that the endogenous MTMR2 and MTMR13 proteins are associated in human embryonic kidney 293 cells. MTMR2-MTMR13 association is mediated by coiled-coil sequences present in each protein. We also examined the cellular localization of MTMR2 and MTMR13 using fluorescence microscopy and subcellular fractionation. We found that (i) MTMR13 is a predominantly membrane-associated protein; (ii) MTMR2 and MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction; and (iii) MTMR13 membrane association is mediated by the segment of the protein which contains the pseudophosphatase domain. This work, which describes the first cellular or biochemical investigation of the MTMR13 pseudophosphatase protein, suggests that MTMR13 functions in association with MTMR2. Loss of MTMR13 function in CMT4B2 patients may lead to alterations in MTMR2 function and subsequent alterations in 3-phosphoinositide signaling. Such a mechanism would explain the strikingly similar phenotypes of patients with recessive mutations in either MTMR2 or MTMR13.


Development and validation of the Somali WHOQOL-BREF among refugees living in the USA.
This study is the first translation and validation of the WHOQOL-BREF for general use in Somali refugee populations. A community sample of 303 Somali refugees living in the USA responded to the WHOQOL-BREF following translation, adaptation, and validation guidelines established by the World Health Organization. Psychometric properties of the quality of life instrument were assessed including tests of the four-domain factor structure using multiple regression and principal component analysis. Principal component analysis demonstrated an acceptable fit between PCA components and original WHOQOL-BREF domains. Four components had eigenvalues greater than one and explained 63.4% of the observed variance. Most scale items loaded like the original WHOQOL-BREF domains, with the notable difference among four items of physical health that loaded more strongly under the environment domain. Construct validity of the scale was confirmed by higher intercorrelations of each WHOQOL-BREF item with its intended domain (all r (2) > 0.50) than with other domains. Multiple regression analyses of the domain scores on overall quality of life (Q1) and health satisfaction (Q2) explained half of the observed variance in each measure. Item correlations showed good internal consistency (0.65 ≥ Cronbach's alpha ≤ 0.82). Validation of this first Somali version of the WHOQOL-BREF provides further evidence that this instrument can be a valid measure for cross-cultural comparative studies of quality of life. Policies that address health disparities can be more broadly evaluated if quality of life is systematically measured in the community. This is particularly important for evaluating policy impact and implications for refugee populations.


The cellular protein P58IPK regulates influenza virus mRNA translation and replication through a PKR-mediated mechanism.
We previously hypothesized that efficient translation of influenza virus mRNA requires the recruitment of P58(IPK), the cellular inhibitor of PKR, an interferon-induced kinase that targets the eukaryotic translation initiation factor eIF2alpha. P58(IPK) also inhibits PERK, an eIF2alpha kinase that is localized in the endoplasmic reticulum (ER) and induced during ER stress. The ability of P58(IPK) to interact with and inhibit multiple eIF2alpha kinases suggests it is a critical regulator of both cellular and viral mRNA translation. In this study, we sought to definitively define the role of P58(IPK) during viral infection of mammalian cells. Using mouse embryo fibroblasts from P58(IPK-/-) mice, we demonstrated that the absence of P58(IPK) led to an increase in eIF2alpha phosphorylation and decreased influenza virus mRNA translation. The absence of P58(IPK) also resulted in decreased vesicular stomatitis virus replication but enhanced reovirus yields. In cells lacking the P58(IPK) target, PKR, the trends were reversed-eIF2alpha phosphorylation was decreased, and influenza virus mRNA translation was increased. Although P58(IPK) also inhibits PERK, the presence or absence of this kinase had little effect on influenza virus mRNA translation, despite reduced levels of eIF2alpha phosphorylation in cells lacking PERK. Finally, we showed that influenza virus protein synthesis and viral mRNA levels decrease in cells that express a constitutively active, nonphosphorylatable eIF2alpha. Taken together, our results support a model in which P58(IPK) regulates influenza virus mRNA translation and infection through a PKR-mediated mechanism which is independent of PERK.


Potential contribution of a novel Tax epitope-specific CD4+ T cells to graft-versus-Tax effect in adult T cell leukemia patients after allogeneic hematopoietic stem cell transplantation.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). We previously reported that Tax-specific CD8(+) cytotoxic T lymphocyte (CTL) contributed to graft-versus-ATL effects in ATL patients after allo-HSCT. However, the role of HTLV-1-specific CD4(+) T cells in the effects remains unclear. In this study, we showed that Tax-specific CD4(+) as well as CD8(+) T cell responses were induced in some ATL patients following allo-HSCT. To further analyze HTLV-1-specific CD4(+) T cell responses, we identified a novel HLA-DRB1*0101-restricted epitope, Tax155-167, recognized by HTLV-1-specific CD4(+) Th1-like cells, a major population of HTLV-1-specific CD4(+) T cell line, which was established from an ATL patient at 180 d after allo-HSCT from an unrelated seronegative donor by in vitro stimulation with HTLV-1-infected cells from the same patient. Costimulation of PBMCs with both the identified epitope (Tax155-167) and known CTL epitope peptides markedly enhanced the expansion of Tax-specific CD8(+) T cells in PBMCs compared with stimulation with CTL epitope peptide alone in all three HLA-DRB1*0101(+) patients post-allo-HSCT tested. In addition, direct detection using newly generated HLA-DRB1*0101/Tax155-167 tetramers revealed that Tax155-167-specific CD4(+) T cells were present in all HTLV-1-infected individuals tested, regardless of HSCT. These results suggest that Tax155-167 may be the dominant epitope recognized by HTLV-1-specific CD4(+) T cells in HLA-DRB1*0101(+)-infected individuals and that Tax-specific CD4(+) T cells may augment the graft-versus-Tax effects via efficient induction of Tax-specific CD8(+) T cell responses.


ZNF300P1 encodes a lincRNA that regulates cell polarity and is epigenetically silenced in type II epithelial ovarian cancer.
We previously identified that the CpG island-associated promoter of the novel lincRNA ZNF300P1 (also known as LOC134466) is frequently hypermethylated and silenced in ovarian cancer tissues. However, the function of ZNF300P1 was unknown. In this report we demonstrate that ZNF300P1 is involved in the regulation of key cell cycle and cell motility networks in human ovarian surface epithelial cells, and may play a role in promoting metastasis in ovarian cancer cells. We applied methylated DNA immunoprecipitation on whole genome promoter tiling arrays and Sequenom assays to examine methylation status of ZNF300P1 in multiple ovarian cancer cell lines, as well as in normal ovarian and ovarian tumor tissues. Transcript profiling was used to investigate the effects of ZNF300P1 suppression in ovarian cancer cells. We utilized siRNA knockdown in normal ovarian surface epithelial cells and performed cellular proliferation, migration and adhesion assays to validate and explore the profiling results. We demonstrate that ZNF300P1 is methylated in multiple ovarian cancer cell lines. Loss of ZNF300P1 results in decreased cell proliferation and colony formation. In addition, knockdown of the ZNF300P1 transcript results in aberrant and less persistent migration in wound healing assays due to a loss of cellular polarity. Using an ex vivo peritoneal adhesion assay, we also reveal a role for ZNF300P1 in the attachment of ovarian cancer cells to peritoneal membranes, indicating a potential function of ZNF300P1 expression in metastasis of ovarian cancer cells to sites within the peritoneal cavity. Our findings further support ZNF300P1 as frequently methylated in ovarian cancer and reveal a novel function for ZNF300P1 lincRNA expression in regulating cell polarity, motility, and adhesion and loss of expression may contribute to the metastatic potential of ovarian cancer cells.


Death receptor 5 signaling promotes hepatocyte lipoapoptosis.
Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Lipoapoptosis by palmitate was not inhibited by a soluble human recombinant DR5-Fc chimera protein suggesting that DR5 cytotoxic signaling is ligand-independent. Hepatocytes from murine TRAIL receptor knock-out mice (DR(-/-)) displayed reduced palmitate-mediated lipotoxicity. Likewise, knockdown of DR5 or caspase-8 expression by shRNA technology attenuated palmitate-induced Bax activation and apoptosis in Huh-7 cells, without altering induction of ER stress markers. Similar observations were verified in other cell models. Finally, knockdown of CHOP, an ER stress-mediated transcription factor, reduced DR5 up-regulation and DR5-mediated caspase-8 activation upon palmitate treatment. Collectively, these results suggest that ER stress-induced CHOP activation by palmitate transcriptionally up-regulates DR5, likely resulting in ligand-independent cytotoxic signaling by this death receptor.


Examining the effect of teleconferences on oncology phase 1 trials.
Phase 1 clinical trials are the first stage of clinical development of an investigational agent. Because the trials often take place at several geographically dispersed sites, safety teleconferences are held to update investigators and the drug sponsor on safety information and other pertinent business related to the trial conduct. Here we examine associations between the frequency of teleconferences and other clinical trial factors on trial conduct efficiency. We examined Phase 1 clinical trials for patients with solid tumors opened for enrollment at a single, non-profit cancer center in Arizona (Center) that had completed at least three dose levels. The following information was included: safety teleconference frequency, whether or not the sponsor or contract research organization sent follow-up requests for updates on patient accrual, and safety outside of scheduled safety teleconferences. The dose escalation scheme, route of study drug administration and formulation type (e.g. oral targeted therapy or monoclonal antibody) was also included. Forty-nine Phase 1 studies were examined for inclusion. The majority of safety teleconferences were regularly scheduled (81.6%) with most taking place bi-weekly (46.9%). Additional solicitation for updates outside of scheduled safety teleconferences were requested during the conduct of 31 (63.3%) studies. None of the factors analyzed were significantly associated with accrual, subject dosing, and dose escalation. We found that the frequency of teleconferences does not appear to expedite phase 1 study accrual, subject dosing, or dose escalation in the first 3 cohorts of a phase 1 clinical trial.


Pseudomonas strains naturally associated with potato plants produce volatiles with high potential for inhibition of Phytophthora infestans.
Bacteria emit volatile organic compounds with a wide range of effects on bacteria, fungi, plants, and animals. The antifungal potential of bacterial volatiles has been investigated with a broad span of phytopathogenic organisms, yet the reaction of oomycetes to these volatile signals is largely unknown. For instance, the response of the late blight-causing agent and most devastating oomycete pathogen worldwide, Phytophthora infestans, to bacterial volatiles has not been assessed so far. In this work, we analyzed this response and compared it to that of selected fungal and bacterial potato pathogens, using newly isolated, potato-associated bacterial strains as volatile emitters. P. infestans was highly susceptible to bacterial volatiles, while fungal and bacterial pathogens were less sensitive. Cyanogenic Pseudomonas strains were the most active, leading to complete growth inhibition, yet noncyanogenic ones also produced antioomycete volatiles. Headspace analysis of the emitted volatiles revealed 1-undecene as a compound produced by strains inducing volatile-mediated P. infestans growth inhibition. Supplying pure 1-undecene to P. infestans significantly reduced mycelial growth, sporangium formation, germination, and zoospore release in a dose-dependent manner. This work demonstrates the high sensitivity of P. infestans to bacterial volatiles and opens new perspectives for sustainable control of this devastating pathogen.


The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation.
Neurofibromatosis-2 is an inherited disorder characterized by the development of benign schwannomas and other Schwann-cell-derived tumors associated with the central nervous system. The Neurofibromatosis-2 tumor suppressor gene encodes Merlin, a member of the Protein 4.1 superfamily most closely related to Ezrin, Radixin and Moesin. This discovery suggested a novel function for Protein 4.1 family members in the regulation of cell proliferation; proteins in this family were previously thought to function primarily to link transmembrane proteins to underlying cortical actin. To understand the basic cellular functions of Merlin, we are investigating a Drosophila Neurofibromatosis-2 homologue, Merlin. Loss of Merlin function in Drosophila results in hyperplasia of the affected tissue without significant disruptions in differentiation. Similar phenotypes have been observed for mutations in another Protein 4.1 superfamily member in Drosophila, expanded. Because of the phenotypic and structural similarities between Merlin and expanded, we asked whether Merlin and Expanded function together to regulate cell proliferation. In this study, we demonstrate that recessive loss of function of either Merlin or expanded can dominantly enhance the phenotypes associated with mutations in the other. Consistent with this genetic interaction, we determined that Merlin and Expanded colocalize in Drosophila tissues and cells, and physically interact through a conserved N-terminal region of Expanded, characteristic of the Protein 4.1 family, and the C-terminal domain of Merlin. Loss of function of both Merlin and expanded in clones revealed that these proteins function to regulate differentiation in addition to proliferation in Drosophila. Further genetic analyses suggest a role for Merlin and Expanded specifically in Decapentaplegic-mediated differentiation events. These results indicate that Merlin and Expanded function together to regulate proliferation and differentiation, and have implications for understanding the functions of other Protein 4.1 superfamily members.


A cathepsin F of adult Clonorchis sinensis and its phylogenetic conservation in trematodes.
A novel 28 kDa cysteine protease (Cs28CF) secreted by the hepatobiliary trematode, Clonorchis sinensis was identified. The protease was purified from the excretory-secretory products (ESP) of the adult worm using DEAE-ion exchange and Arginine-Sepharose 4B chromatography. It showed a high activity between pH 6.5 and 7.5 in a dithiothreitol (DTT)-dependent manner. Inhibitors specific to cysteine proteases down-regulated the activity. Addition of Cs28CF to monkey cholangiocyte cultures resulted in approximately 95% cell death after 7 days. The full-length cDNA (1078 bp) encoded a single peptide of 328 amino acids (aa) with an N-terminal hydrophobic sequence, an ERFNAQ motif in the propeptide and a mature domain. Expression of mRNA transcripts of Cs28CF was observed in both the metacercaria and adult stages. Bacterially expressed recombinant protein exhibited a specific antibody reaction with clonorchiasis sera. Deduced aa exhibited 52-76% sequence identity with the cathepsin F analogues from other organisms. A novel E/DXGTA motif was recognized in the propeptide region. Phylogenetic analysis of 63 papain family members revealed that the trematode cysteine proteases formed 2 major clades of cathepsins F and L. The trematode cysteine proteases classified as cathepsin F shared higher homology among themselves than those classified as cathepsin L. Cathepsin F is phylogenetically conserved in the trematode parasites as well as in mammals.


Combination of radon and stable isotope analysis as a tool for decision support concerning the remediation of NAPL-contaminated sites.
The non-aqueous phase-liquid (NAPL)-contaminated aquifer at a major refinery site in Mexico was investigated. Owing to the depth of the contaminated aquifer section (NAPL source zone) of over 100 m below the surface, the actual aquifer material was not accessible for sampling. Information on the residual NAPL contamination of the aquifer could only be obtained indirectly by analysing groundwater samples from a few wells available at the site. To tackle the problem, an approach alternative to conventional groundwater analysis for dissolved NAPL was chosen. For evaluating the recent contamination and estimating its probable future development, the radioisotope radon-222 and the stable isotopes 13C, 34S and 18O were used as naturally occurring contamination tracers and process indicators. Radon was used as partitioning tracer for the approximate localization and semi-quantitative assessment of the NAPL source zone. The stable isotopes were used as indicators for naturally occurring biodegradation processes, which might potentially be implemented into future remediation schemes.


Inferring microRNA and transcription factor regulatory networks in heterogeneous data.
Transcription factors (TFs) and microRNAs (miRNAs) are primary metazoan gene regulators. Regulatory mechanisms of the two main regulators are of great interest to biologists and may provide insights into the causes of diseases. However, the interplay between miRNAs and TFs in a regulatory network still remains unearthed. Currently, it is very difficult to study the regulatory mechanisms that involve both miRNAs and TFs in a biological lab. Even at data level, a network involving miRNAs, TFs and genes will be too complicated to achieve. Previous research has been mostly directed at inferring either miRNA or TF regulatory networks from data. However, networks involving a single type of regulator may not fully reveal the complex gene regulatory mechanisms, for instance, the way in which a TF indirectly regulates a gene via a miRNA. We propose a framework to learn from heterogeneous data the three-component regulatory networks, with the presence of miRNAs, TFs, and mRNAs. This method firstly utilises Bayesian network structure learning to construct a regulatory network from multiple sources of data: gene expression profiles of miRNAs, TFs and mRNAs, target information based on sequence data, and sample categories. Then, in order to produce more meaningful results for further biological experimentation and research, the method searches the learnt network to identify the interplay between miRNAs and TFs and applies a network motif finding algorithm to further infer the network.We apply the proposed framework to the data sets of epithelial-to-mesenchymal transition (EMT). The results elucidate the complex gene regulatory mechanism for EMT which involves both TFs and miRNAs. Several discovered interactions and molecular functions have been confirmed by literature. In addition, many other discovered interactions and bio-markers are of high statistical significance and thus can be good candidates for validation by experiments. Moreover, the results generated by our method are compact, involving a small number of interactions which have been proved highly relevant to EMT. We have designed a framework to infer gene regulatory networks involving both TFs and miRNAs from multiple sources of data, including gene expression data, target information, and sample categories. Results on the EMT data sets have shown that the proposed approach is able to produce compact and meaningful gene regulatory networks that are highly relevant to the biological conditions of the data sets. This framework has the potential for application to other heterogeneous datasets to reveal the complex gene regulatory relationships.


Pointwise linear regression analysis of serial Humphrey visual fields and a correlation with electroretinography in birdshot chorioretinopathy.
To investigate deterioration in serial Humphrey visual fields (HVFs) using pointwise linear regression (PLR) analysis in patients with birdshot chorioretinopathy (BCR) monitored with full field electroretinography (ERG). Retrospective review of the case notes, HVFs and ERG of patients under treatment for BCR at Moorfields Eye Hospital between 1998 and 2014. Eyes with ERG recorded using protocols to incorporate International Society for Clinical Electrophysiology of Vision standards and at least five reliable Swedish Interactive Testing Algorithm standard 24-2 HVFs were included. HVFs were analysed by PLR analysis of luminance sensitivity using the Progressor software and linear regression analysis of mean deviation (MD). 202 HVFs from 31 eyes of 16 patients were analysed. Mean follow-up was 60.25 months. MD remained stable in all eyes. PLR analysis detected progressive field loss in 10 eyes (seven patients). The mean (SD) slope of change at progressing points was -1.83 (0.90) db/year (p<0.05). ERG worsened in 3 of the 10 eyes with field loss. Although there was no clear relationship between patterns of field loss and electrophysiological dysfunction, more extensive field loss was associated with more marked ERG abnormalities and rod system involvement. This study demonstrates that PLR analysis can identify field loss despite a stable MD and stable and even normal electrophysiology in BCR, thus establishing a role for regular standardised monitoring of visual fields as an adjunct to electrophysiology in order to facilitate more accurate characterisation of retinal dysfunction and hence enabling better-informed treatment decisions and monitoring of treatment efficacy.


Androgen deprivation therapy for prostate cancer.
Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in US men. Androgen deprivation therapy (ADT), specifically surgical or medical castration, is the first line of treatment against advanced prostate cancer and is also used as an adjuvant to local treatment of high-risk disease. To review systematically the evidence on the risks and benefits of ADT for prostate cancer as well as clinical management of its adverse effects. We performed MEDLINE searches of English-language literature (1966 to March 2005) using the terms androgen deprivation therapy, hormone treatment, and prostate cancer. We reviewed bibliographies of literature to extract other relevant articles. Studies were selected based on clinical pertinence, with an emphasis on controlled study design. Androgen deprivation therapy is effective for palliation in many patients with advanced prostate cancer and improves outcomes for high-risk patients treated with radiation therapy for localized disease. Although patients with increasing prostate-specific antigen levels after local treatment without metastatic disease frequently undergo ADT, the benefits of this strategy are not clear. Adverse effects of ADT include decreased libido, impotence, hot flashes, osteopenia with increased fracture risk, metabolic alterations, and changes in cognition and mood. Androgen deprivation therapy has clear roles in the management of advanced prostate cancer and high-risk localized disease. The benefits of ADT in other settings need to be weighed carefully against substantial risks and adverse effects on quality of life.


Morphological, Mechanical and Mucoadhesive Properties of Electrospun Chitosan/Phospholipid Hybrid Nanofibers.
This study aimed to develop hybrid electrospun chitosan⁻phospholipid nanofibers and investigate the effect of phospholipid (P) content and chitosans (Ch) molecular weights (Mw) and degree of acetylation (DA), on the morphological, mechanical and mucoadhesive properties of the nanofibers. Electrospun Ch/P nanofibers exhibited a smooth and uniform surface with average diameters ranging from 300 to 1000 nm, as observed by scanning electron microscopy (SEM). The average diameter of the nanofibers was observed to increase with the increase of the Mw and degree of deacetylation of Ch, and phospholipid content. The elastic and adhesive properties of the nanofibers were determined by atomic force microscopy, and displayed higher values for higher Mw and lower DA Ch used. The elastic modulus of electrospun Ch/P hybrid fibers determined for the different conditions tested was found to be in the range of 500 and 1400 MPa. Furthermore, electrospun Ch/P nanofibers displayed mucoadhesive properties expressed by the work of adhesion calculated after the compression of the nanofibers against a section of pig small intestine. Our results showed that the increase in phospholipid content and DA of Ch decrease the work of adhesion, while the increase of Mw resulted in slightly higher work of adhesion of the nanofibers.


Molecular characterisation of a hypervariable region downstream of the human alpha-globin gene cluster.
We have characterised an unusual, highly polymorphic region of DNA located 8-kb downstream of the human alpha-globin gene complex. This hypervariable region (alpha-globin 3' HVR) is composed of an array of 17-bp tandem repeats, the number of which differs considerably (70-450) from one allele to another. The sequence of the 17-bp repeats is highly conserved within and between alleles. Furthermore, this sequence identifies a core oligonucleotide [5'-GNGGGG(N)ACAG-3'] that is common to three previously characterised hypervariable regions. At reduced stringency, a probe to the 3' HVR detects a new family of multiallelic loci that will be of value in the study of human genetics.


What executives should remember.
In more than 30 essays for Harvard Business Review, Peter Drucker (1909-2005) urged readers to take on the hard work of thinking--always combined, he insisted, with decisive action. He closely analyzed the phenomenon of knowledge work--the growing call for employees who use their minds rather than their hands--and explained how it challenged the conventional wisdom about the way organizations should be run. He was intrigued by employees who knew more about certain subjects than their bosses or colleagues but who still had to cooperate with others in a large organization. As the business world matured in the second half of the twentieth century, executives came to think that they knew how to run companies--and Drucker took it upon himself to poke holes in their assumptions, lest organizations become stale. But he did so sympathetically, operating from the premise that his readers were intelligent, hardworking people of goodwill. Well suited to HBR's format of practical, idea-based essays for executives, his clear-eyed, humanistic writing enriched the magazine time and again. This article is a compilation of the savviest management advice Drucker offered HBR readers over the years--in short, his greatest hits. It revisits the following insightful, influential contributions: "The Theory of the Business" (September-October 1994), "Managing for Business Effectiveness" (May-June 1963), "What Business Can Learn from Nonprofits" (July-August 1989), "The New Society of Organizations" (September-October 1992), "The Information Executives Truly Need" (January-February 1995), "Managing Oneself" (March-April 1999 republished January 2005), "They're Not Employees, They're People" (February 2002), "What Makes an Effective Executive" (June 2004).


Interinstitutional comparison of frozen section turnaround time. A College of American Pathologists Q-Probes study of 32868 frozen sections in 700 hospitals.
To study the intraoperative turnaround time for performing a frozen section (FS) and to examine pathology practice variables that influence it. Over a 4-month period in 1995, participants in the College of American Pathologists Q-Probes laboratory quality improvement program prospectively collected data on up to 30 FS procedures performed on elective inpatient surgical cases and completed questionnaires profiling their FS practice characteristics. Surgical pathology laboratories serving private and public hospitals. Seven hundred institutions located in North America (667), Australia (12), New Zealand (1), the United Kingdom (3), Hong Kong (1), Mexico (1), and Norway (1). The 90% FS block completion time defined as the time interval, in minutes, within which the fastest 90% of all FS blocks were completed, measured from the time pathologists received FS specimens to the time they communicated FS results to the surgeon. Participants submitted data on 32868 FS blocks. Ninety percent of FS procedures were completed within 20 minutes. Frozen section turnaround times exceeding 20 minutes, termed outlier turnaround times, were more likely to occur when more than one pathologist participated in the FS diagnosis, pathology residents and medical students participated in the FS procedure, the pathologist had to retrieve and review previous case material during the FS procedure, the pathologist simultaneously received additional specimens from other FS cases, the pathologist was unable to reach a final FS diagnosis, and when technical problems occurred during the FS procedure. Seventy percent of all participating hospitals completed 90% of their frozen sections within 20 minutes. The institutional 90% completion times were shorter for hospitals containing 300 or fewer occupied beds than for those containing more than 300 occupied beds. The data suggest that 90% of FS block turnaround times can be performed within 20 minutes, measured from the time that pathologists receive FS specimens to the time that pathologists return FS diagnoses to surgeons.


SU-E-T-488: Dose Calculation Model Using the Simplified Monte Carlo Method with an Initial Beam Model Adapted to a Beam-Wobbling System.
We have developed an accurate dose calculation model based on a simplified Monte Carlo (SMC) method adapted to a beam-wobbling delivery system at National Cancer Center Hospital East (NCCHE). We used an initial beam model specific to the beam-wobbling system to reproduce accurately different dose distributions in two lateral directions (x- and y-directions) perpendicular to each other. The SMC calculates a dose distribution by tracking individual protons. The SMC starts tracking protons at an entrance of a range compensator. Protons are generated in an initial phase space adapted to the wobbler system. Since two wobbling-magnets are located at separate places with different distances from the iso-center, different dose distributions are formed in x- and y-directions. We derived an initial phase space distribution for the beam-wobbling system using an analytical method. We used the SMC method with the initial beam model to calculate dose distributions accurately. To verify accuracy of the calculation method, we measured the dose distribution in a homogeneous phantom formed by 235 MeV protons passing through a L-shaped range compensator. We used a 2D-array of parallel-plate ionization chambers (2D Array seven29®) to measure dose distributions with a sampling period of 5 mm. The measured dose distribution in the x-direction was different from that in the y-direction. Our calculation model reproduces the measurement results well in both lateral directions. In addition, the calculation reproduced the dose increments in edge regions contributed by edge-scattered protons in collimator. It indicates the advantage of the SMC. A dose calculation model has been developed based on the simplified Monte Carlo method applied to a beam-wobbling system. By adapting the initial beam model to the wobbling system, the SMC method is found to reproduce observed different dose distributions in x- and y-directions well.


Chemoprevention meets glucose control.
The report by Memmott et al. (beginning on page 1066 in this issue of the journal) assessing the efficacy of the antidiabetes drug metformin in a mouse model of lung carcinogenesis suggests protective effects via two possible avenues: Decreased circulating insulin and insulin-like growth factor levels and energy stress leading to inhibition of mammalian target of rapamycin signaling. These potential mechanisms are discussed in this perspective, as are their implications for cancer prevention and therapy.


Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study.
Therapy of hairy cell leukemia has markedly improved. Interferon alfa-2a and pentostatin are active agents. The National Cancer Institute organized an intergroup trial to compare these agents prospectively in untreated patients. Patients were randomized to receive either interferon alfa-2a (3 x 10(6) U subcutaneously three times per week) or pentostatin (4 mg/m2 intravenously every 2 weeks). Patients who did not respond to initial treatment were crossed over. Of 356 patients on study, 313 were eligible. Among interferon patients, 17 of 159 (11%) achieved a confirmed complete remission and 60 of 159 (38%) had a confirmed complete or partial remission. Among pentostatin patients, 117 of 154 (76%) achieved a confirmed complete remission and 121 of 154 (79%) had a confirmed complete or partial remission. Additional patients achieved criteria for complete remission, but lacked confirmatory follow-up evaluation. Response rates were significantly higher (P < .0001) and relapse-free survival was significantly longer with pentostatin than interferon (P < .0001). The median follow-up duration is 57 months (range, 19 to 82). Myelosuppression was more frequent with pentostatin (P = .013). A multivariate logistic regression analysis of the confirmed complete remissions on pentostatin showed the following factors to be important for achieving a complete remission: high hemoglobin level (two-tailed P = .024), young age (P = .0085), and no or little splenomegaly (P = .0029). Both agents were well tolerated. Pentostatin produced higher response rates, and the responses were durable. Patient age and clinical status had an impact on outcome with pentostatin. Pentostatin is effective therapy for hairy cell leukemia.


Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis and management.
Reports of corticosteroid-induced adverse psychiatric effects began to appear in the literature soon after the introduction of these medications in the 1950s. Unfortunately, early studies relied on informal classification and measurement procedures and tended to utilise nonspecific descriptive terminology (such as steroid psychosis'). A growing number of contemporary investigations have begun to address these problems. However, the literature remains surprisingly undeveloped from a pharmacoepidemiological perspective, consisting largely of case reports and case series. The objective of this review is to summarise published data concerning corticosteroid-induced adverse psychiatric effects. A clinical perspective will be adopted since opportunities to minimise the impact of corticosteroid-induced adverse effects tend to present themselves most readily within the sphere of clinical management. Some of the psychiatric adverse effects of corticosteroids are mild, and not necessarily clinically significant. However, several serious psychiatric syndromes can be caused by corticosteroids: substance-induced mood disorders (with depressive, manic and mixed features), substance-induced psychotic disorders and delirium. While certain clinical groups may be at greater risk of corticosteroid-induced adverse psychiatric effects, corticosteroid-induced psychiatric toxicity is remarkably unpredictable. The literature regarding prevention and treatment of corticosteroid-induced adverse psychiatric effects is poorly developed. As a result, the emphasis of this review is on clinical and epidemiological evidence linking specific adverse effects to corticosteroid medications. However, clinical reports do provide some practical guidance for prevention and treatment, and these are summarised as well. A variety of pharmacological strategies for treatment and prevention have been proposed. Education and support also appear to be important, and perhaps neglected.


General theory of sub-quarterwave multilayers with highly absorbing materials.
A general theory of multilayers with enhanced reflectance has been developed based on the superposition of sub-quarterwave layers of various highly radiation-absorbing materials. The theory has been developed by second-order expansion of the multilayer reflectance with respect to the optical-constant differences between the materials in the multilayer. The current paper completes and improves the theory that was developed in a previous paper [J. Opt. Soc. Am. A 18, 1406 (2001)] by including the case of nonnormal incidence and general radiation polarization and by providing more-accurate film thickness values of the optimized multilayer than with the previous theory. The theory provides an accurate approach to the design of a new concept of multilayer coatings with more than two materials. The new multilayers are adequate to enhance the reflectance of the materials particularly in the far and the extreme ultraviolet.


Results From Poland's 2016 Report Card on Physical Activity for Children and Youth.
Poland's 2016 Report Card on Physical Activity for Children and Youth is the first assessment of child and youth physical activity (PA) in Poland using the Active Healthy Kids Global Alliance grading system. The main goal was to summarize and describe the current state of child and youth PA to increase awareness and surveillance. The systematic methodology that underpins the Active Healthy Kids Canada Report Card was adapted and applied to the Polish report card. The best available data were consolidated, reviewed by a group of experts, and used to assign the letter grades to 9 core PA indicators on a scale ranging from A (highest) to F (lowest). The 9 indicators were graded as such: 1) Overall Physical Activity (D), 2) Organized Sport Participation (C), 3) Active Play (INC), 4) Active Transportation (C), 5) Sedentary Behaviors (D), 6) Family and Peers (C), 7) School (B), 8) Community and the Built Environment (C), and 9) Government Strategies and Investments (C). The final grades show a strong role of school in providing PA for children and youth in Poland. However, promotion of school-based sport participation appears to be insufficient by itself to sustainably promote PA in this group.


[The study of telomere length in patients with Parkinson's disease].
Telomeres which are formed by double-strand breaks and DNA under replication, cause cell cycle arrest resulting in cellular senescence and apoptosis. The erosion of telomeres is an important mechanism for regulating the aging process by limiting cell proliferation. Over the last decade, many investigations in the field of telomeric biology showed that telomeric DNA and telomeric proteins are involved in the pathogenesis of some human diseases. The aim of the study was to compare telomere length in patients with Parkinson's disease (PD). Telomere length was measured in buccal epithelial cells and leukocytes in PD patients and controls. The length of telomeres in cells of buccal epithelium was shorter in patients with PD than in the control group. In blood cells, telomere length did not differ. It is suggested that shortening of telomeres in buccal epithelial cells may be due to oxidative stress and, hence, it can be used as a marker for the early stages of disease.


Derivation of research diagnostic criteria for insomnia: report of an American Academy of Sleep Medicine Work Group.
Insomnia is a highly prevalent, often debilitating, and economically burdensome form of sleep disturbance caused by various situational, medical, emotional, environmental and behavioral factors. Although several consensually-derived nosologies have described numerous insomnia phenotypes, research concerning these phenotypes has been greatly hampered by a lack of widely accepted operational research diagnostic criteria (RDC) for their definition. The lack of RDC has, in turn, led to inconsistent research findings for most phenotypes largely due to the variable definitions used for their ascertainment. Given this problem, the American Academy of Sleep Medicine (AASM) commissioned a Work Group (WG) to review the literature and identify those insomnia phenotypes that appear most valid and tenable. In addition, this WG was asked to derive standardized RDC for these phenotypes and recommend assessment procedures for their ascertainment. This report outlines the WG's findings, the insomnia RDC derived, and research assessment procedures the WG recommends for identifying study participants who meet these RDC.


Relative contribution of sequence and structure features to the mRNA binding of Argonaute/EIF2C-miRNA complexes and the degradation of miRNA targets.
How miRNAs recognize their target sites is a puzzle that many experimental and computational studies aimed to solve. Several features, such as perfect pairing of the miRNA seed, additional pairing in the 3' region of the miRNA, relative position in the 3' UTR, and the A/U content of the environment of the putative site, have been found to be relevant. Here we have used a large number of previously published data sets to assess the power that various sequence and structure features have in distinguishing between putative sites that do and those that do not appear to be functional. We found that although different data sets give widely different answers when it comes to ranking the relative importance of these features, the sites inferred from most transcriptomics experiments, as well as from comparative genomics, appear similar at this level. This suggests that miRNA target sites have been selected in evolution on their ability to trigger mRNA degradation. To understand at what step in the miRNA-induced response individual features play a role, we transfected human HEK293 cells with miRNAs and analyzed the association of Argonaute/EIF2C-miRNA complexes with target mRNAs and the degradation of these messages. We found that structural features of the target site are only important for Argonaute/EIF2C binding, while sequence features such as the A/U content of the 3' UTR are important for mRNA degradation.


High RF carrier frequency modulation in silicon resonators by coupling adjacent free-spectral-range modes.
We demonstrate the modulation of silicon ring resonators at RF carrier frequencies higher than the resonance linewidth by coupling adjacent free-spectral-range (FSR) resonance modes. In this modulator scheme, the modulation frequency is matched to the FSR frequency. As an example, we demonstrate a 20 GHz modulation in a silicon ring with a resonance linewidth of only 11.7 GHz. We show theoretically that this modulator scheme has lower power consumption compared to a standard silicon ring modulator at high carrier frequencies. These results could enable future on-chip high-frequency analog communication and photonic signal processing on a silicon photonics platform.


Gonadotropin-releasing hormone-regulated chemokine expression in human placentation.
Placental expression of gonadotropin-releasing hormone (GnRH)-I and II, as well as their cognate receptor, coincides with a period of extensive remodeling of the maternal-fetal interface, near the end of the first trimester of pregnancy. To further define the role of GnRH in human placentation, we performed a microarray screen of HTR-8/SVneo trophoblasts to identify GnRH-regulated genes and their roles in placentation. This screen revealed that GnRH regulates the expression of four angiogenic chemokines: CXCL2, CXCL3, CXCL6, and CXCL8. The microarray data were subsequently confirmed by an extensive Q-PCR time-course analysis. CXCL8, a representative chemokine, was selected for further analysis and shown to be strongly expressed by trophoblasts at the maternal-fetal interface of the human placenta, as well as to accumulate in a GnRH-dependent manner in trophoblast-conditioned media in culture. Trophoblasts were subsequently shown to recruit lymphocytes (Jurkat T cells and primary peripheral blood T and uterine natural killer cells) in chemotaxis assays and this was shown to be GnRH dependent. Furthermore, this recruitment was shown to occur via the release of CXCR1/CXCR2 interacting chemokines, such as the CXCLs investigated in this study. This novel regulation of chemokines by GnRH signaling demonstrates the role of GnRH in regulating the recruitment of lymphocytes to the decidua and the possibility of a direct effect on spiral artery remodeling via the release of proangiogenic chemokines and secondary effects via release of angiogenic factors by recruited lymphocytes.


Structure/function studies of HIV-1(1) reverse transcriptase: dimerization-defective mutant L289K.
Virion-derived HIV-1 reverse transcriptase (RT) has subunits of molecular mass 66 and 51 kDa (p66 and p51, respectively) in an approximately 1:1 ratio. Since enzyme activity appears to depend on dimerization of these subunits, identification of critical regions of primary sequence required for proper dimerization could lead to potential targets for antiviral therapy. A central region of primary sequence contains a leucine hepta-repeat motif from leucine 282 to leucine 310 that has been suggested to be involved in dimerization [Baillon, J. G., Nashed, N. T., Kumar, A., Wilson, S. H., & Jerina, D. M. (1991) New Biol. 3, 1015-1019]. A region including this hepta-repeat was recently shown to be involved in protein-protein interactions required for dimerization [Becerra, S. P., Kumar, A., Lewis, M. S., Widen, S. G., Abbotts, J., Karawya, E. M., Hughes, S. H., Shiloach, J., & Wilson, S. H. (1991) Biochemistry 30, 11708-11719]. To investigate the role of this repeat motif in dimerization, we performed site-directed mutagenesis of these leucine residues from position 282 to position 310. Mutations were introduced into p66 and p51 RT coding sequences, and the individually purified RT subunit polypeptides were compared with wild-type polypeptides for dimerization. Physical characterization of the purified mutant peptides was conducted by circular dichroism analysis. Binding between p66 and p51 was studied by gel filtration, ultracentrifugation, and CD analysis. L289K-p66 was unable to dimerize with itself and wild-type or L289K-p51. The leucine repeat motif in the p66 subunit appears to be critical in formation of the heterodimer.(ABSTRACT TRUNCATED AT 250 WORDS)


Human Infection with Orf Virus and Description of Its Whole Genome, France, 2017.
Zoonotic transmission of parapoxvirus from animals to humans has been reported; clinical manifestations are skin lesions on the fingers and hands after contact with infected animals. We report a human infection clinically suspected as being ecthyma contagiosum. The patient, a 65-year-old woman, had 3 nodules on her hands. She reported contact with a sheep during the Aïd-el-Fitr festival in France during 2017. We isolated the parapoxvirus orf virus from these nodules by using a nonconventional cell and sequenced the orf genome. We identified a novel orf virus genome and compared it with genomes of other orf viruses. More research is needed on the genus Parapoxvirus to understand worldwide distribution of and infection by orf virus, especially transmission between goats and sheep.


Differences in child versus parent reports of the child's health-related quality of life in children with epilepsy and healthy siblings.
Self versus proxy perspectives may produce different results that are important for clinical decision-making and for assessing outcomes in research studies. We examined differences in child versus parent report of the child's health-related quality of life (HRQOL) in a large prospective, community-based study of newly diagnosed childhood epilepsy that included children with epilepsy (case) and sibling controls. HRQOL was assessed 8 to 9 years after initial diagnosis of epilepsy in a subset of 143 case-control matched pairs using the Child Health Questionnaire (CHQ), a generic HRQOL measure with child (CHQ-CF87), and parent (CHQ-PF50) versions. There were no significant differences between self-reported case and sibling control HRQOL scores on 9 of 11 scales or 2 global items. Nevertheless, parent ratings were significantly better (higher HRQOL) for sibling controls compared with epilepsy cases on 10 of 12 scales, global behavior and general health items, and the physical and psychosocial summary scores (P≤0.05). Parent-child agreement was low for cases and controls (kappa 0.27-0.33) for three single-item questions with the same wording on parent and child versions. Parent ratings of the case's HRQOL were often significantly associated with 5-year remission status and current antiepileptic drug use, but the case's self-reported HRQOL scores were not. In contrast, current pharmacoresistance was often associated with the child and parent ratings of the child's HRQOL. Children with epilepsy report HRQOL that is comparable to that of sibling controls, while parents rate children with epilepsy as having lower HRQOL than sibling controls. Measuring outcomes in studies of this population should incorporate both perspectives.


Clinical stain removal efficacy of two dentifrices after one and two weeks of use.
This investigation evaluated extrinsic stain removal efficacy after brushing for one and two weeks with a commercially available fluoride dentifrice relative to Colgate Total Advanced Clean, a new dentifrice formulated with dual-phase silica. At the baseline visit, one-hundred and forty-four adult subjects were stratified by Lobene Stain Index scores and randomized to two treatment groups using either Total Advanced Clean dentifrice (0.3% triclosan, 2% copolymer, dual phase silica) or a commercially available fluoride dentifrice, and instructed to brush twice daily. Tooth stain evaluations were conducted on stain area, stain intensity, and a composite score of both, after one and two weeks of dentifrice use. Baseline scores demonstrated no significant differences between the two treatment groups for all evaluated stain parameters (p > 0.05). At both the one- and two-week post-use evaluations, subjects brushing with Total Advanced Clean demonstrated significant reductions for all stain parameters versus the control (p < 0.05). The Total Advanced Clean group demonstrated mean reductions in stain intensity of 0.37 and 0.74 at the one- and two-week evaluations, respectively, versus the control group. Corresponding mean reductions in stain area for the Total Advanced Clean group versus the control were 0.12 and 0.24 at the one- and two-week evaluations, respectively. The two post-use evaluations also demonstrated significant reductions in stain composite scores for the subjects assigned Total Advanced Clean (p < 0.0001). In comparison to the control dentifrice, the results demonstrated significantly more stain removal following the use of Total Advanced Clean at each recall visit. Subjects assigned Total Advanced Clean demonstrated continued reductions in stains from baseline to one week, and from one week to two weeks.


Insight into the mechanism of antimicrobial poly(phenylene ethynylene) polyelectrolytes: interactions with phosphatidylglycerol lipid membranes.
The interactions of antimicrobial poly(phenylene ethynylene) (PPE)-based cationic conjugated polyelectrolytes (CPEs) with lipid membranes were investigated to gain insight into the mechanism of their biocidal activity. Three model membrane systems comprising negatively charged phosphatidylglycerol (PG) lipids were used to mimic the bacterial cell membrane, including unilamellar lipid vesicles in aqueous solution, lipid bilayer coated silica microspheres, and lipid monolayers at the air-water interface. Two PPE CPEs, one containing a thiophene moiety on the PPE repeat unit and the second containing a diazabicyclooctane (DABCO) moiety on the pendant side chain, were chosen, since the former exhibits distinct dark biocidal activity and the latter shows strong light-activated antimicrobial activity but little dark biocidal activity. The interactions of these two PPE polymers with lipid membranes were characterized in detail by CPE fluorescence spectral changes, fluorescence resonance energy transfer (FRET), fluorescence quenching, monolayer insertion, and dynamic light scattering assays. Both PPE polymers exhibit affinity for the anionic lipid membrane systems. Their concomitant association and insertion into the membrane leads to conformational changes of the PPE polymer from an aggregated state to a more extended state, as evidenced by the polymer's enhanced fluorescence and FRET between the polymer and rhodamine incorporated in the lipid membrane. In comparison, the thiophene polymer exhibits stronger interactions with PG lipid membranes than the DABCO-containing polymer. The former induces a larger fluorescence enhancement, shows faster transfer across the lipid membrane, and inserts more readily and to a higher extent into lipid monolayers. The observed differences between the two PPE polymers in their interactions with the lipid membrane may stem from their structural differences, as the DABCO-containing polymer has a much bulkier and larger pendant group on its side chain. The higher degree of membrane interaction and insertion, and subsequent membrane disorganization, of the thiophene polymer may account for its dark biocidal activity.


Systematic review of prognostic models for recurrent venous thromboembolism (VTE) post-treatment of first unprovoked VTE.
To review studies developing or validating a prognostic model for individual venous thromboembolism (VTE) recurrence risk following cessation of therapy for a first unprovoked VTE. Prediction of recurrence risk is crucial to informing patient prognosis and treatment decisions. The review aims to determine whether reliable prognostic models exist and, if not, what further research is needed within the field. Bibliographic databases (including MEDLINE, EMBASE and the Cochrane Library) were searched using index terms relating to the clinical field and prognosis. Screening of titles, abstracts and subsequently full texts was conducted by 2 reviewers independently using predefined criteria. Quality assessment and critical appraisal of included full texts was based on an early version of the PROBAST (Prediction study Risk Of Bias Assessment Tool) for risk of bias and applicability in prognostic model studies. Studies in any setting were included. The primary outcome for the review was the predictive accuracy of identified prognostic models in relation to VTE recurrence risk. 3 unique prognostic models were identified including the HERDOO2 score, Vienna prediction model and DASH score. Quality assessment highlighted the Vienna, and DASH models were developed with generally strong methodology, but the HERDOO2 model had many methodological concerns. Further, all models were considered at least at moderate risk of bias, primarily due to the need for further external validation before use in practice. Although the Vienna model shows the most promise (based on strong development methodology, applicability and having some external validation), none of the models can be considered ready for use until further, external and robust validation is performed in new data. Any new models should consider the inclusion of predictors found to be consistently important in existing models (sex, site of index event, D-dimer), and take heed of several methodological issues identified through this review. CRD42013003494.


PKC in motorneurons underlies self-learning, a form of motor learning in Drosophila.
Tethering a fly for stationary flight allows for exquisite control of its sensory input, such as visual or olfactory stimuli or a punishing infrared laser beam. A torque meter measures the turning attempts of the tethered fly around its vertical body axis. By punishing, say, left turning attempts (in a homogeneous environment), one can train a fly to restrict its behaviour to right turning attempts. It was recently discovered that this form of operant conditioning (called operant self-learning), may constitute a form of motor learning in Drosophila. Previous work had shown that Protein Kinase C (PKC) and the transcription factor dFoxP were specifically involved in self-learning, but not in other forms of learning. These molecules are specifically involved in various forms of motor learning in other animals, such as compulsive biting in Aplysia, song-learning in birds, procedural learning in mice or language acquisition in humans. Here we describe our efforts to decipher which PKC gene is involved in self-learning in Drosophila. We also provide evidence that motorneurons may be one part of the neuronal network modified during self-learning experiments. The collected evidence is reminiscent of one of the simplest, clinically relevant forms of motor learning in humans, operant reflex conditioning, which also relies on motorneuron plasticity.


Transition-Metal-Free Oxidative Cross-Coupling of Triorganoindium Reagents with Tetrahydroisoquinolines.
Triorganoindium reagents (R3In) react with tetrahydroisoquinolines (THIQs) in the presence of Ph3CBF4 as an oxidant to afford 1-substituted THIQs. The reaction proceeds in good yields at rt using 50 mol % R3In with a variety of organic groups. 1H NMR studies show the generation of an iminium ion intermediate, supporting a two-step mechanism based on THIQ oxidation and R3In nucleophilic addition. This reaction was applied to the synthesis of the alkaloid nuciferine in three steps.


Participatory research to design a novel telehealth system to support the night-time needs of people with dementia: NOCTURNAL.
Strategies to support people living with dementia are broad in scope, proposing both pharmacological and non-pharmacological interventions as part of the care pathway. Assistive technologies form part of this offering as both stand-alone devices to support particular tasks and the more complex offering of the "smart home" to underpin ambient assisted living. This paper presents a technology-based system, which expands on the smart home architecture, orientated to support people with daily living. The system, NOCTURNAL, was developed by working directly with people who had dementia, and their carers using qualitative research methods. The research focused primarily on the nighttime needs of people living with dementia in real home settings. Eight people with dementia had the final prototype system installed for a three month evaluation at home. Disturbed sleep patterns, night-time wandering were a focus of this research not only in terms of detection by commercially available technology but also exploring if automated music, light and visual personalized photographs would be soothing to participants during the hours of darkness. The NOCTURNAL platform and associated services was informed by strong user engagement of people with dementia and the service providers who care for them. NOCTURNAL emerged as a holistic service offering a personalised therapeutic aspect with interactive capabilities.


Are PPIs beneficial for nasal polyps?
A new Annals feature in 2018, "From the Pages of AllergyWatch" is devoted to publishing synopses of Allergy and Asthma literature relevant to a topic of emphasis. These unbiased synopses and comments by our Editors have been previously printed in the AllergyWatch bimonthly newsletter, and it is our hope that presenting carefully selected article summaries and comments in the Annals will serve as a valuable educational resource for practicing allergists.


Observation of decreased radiation damage at higher dose rates in room temperature protein crystallography.
Radiation damage can be a problem when utilizing ionizing X-radiation in macromolecular crystallography. The dose dependence of radiation damage to eight lysozyme crystals at room temperature (292 K) was investigated in order to provide an accurate comparison with cryotemperature (100 K) results and to allow researchers to calculate expected maximum room-temperature-crystal lifetimes prior to data collection. Results of intensity-loss analysis unexpectedly showed that the dose tolerated by a crystal is dependent on the dose rate according to a positive linear relationship (99% correlation coefficient); a 60% increase in dose rate gave a 4-fold increase in crystal lifetime over the range studied. Alternative metrics of damage were also assessed from room temperature data. In the dose-rate range tested (6 Gy s(-1) to 10 Gy s(-1)), data collection at 100 K appears to offer a 26-113 times increase in the lifetime of the crystal.


Activation of Matrix Metalloproteinase-3 is altered at the frog neuromuscular junction following changes in synaptic activity.
The extracellular matrix surrounding the neuromuscular junction is a highly specialized and dynamic structure. Matrix Metalloproteinases are enzymes that sculpt the extracellular matrix. Since synaptic activity is critical to the structure and function of this synapse, we investigated whether changes in synaptic activity levels could alter the activity of Matrix Metalloproteinases at the neuromuscular junction. In particular, we focused on Matrix Metalloproteinase 3 (MMP3), since antibodies to MMP3 recognize molecules at the frog neuromuscular junction, and MMP3 cleaves a number of synaptic basal lamina molecules, including agrin. Here we show that the fluorogenic compound (M2300) can be used to perform in vivo proteolytic imaging of the frog neuromuscular junction to directly measure the activity state of MMP3. Application of this compound reveals that active MMP3 is concentrated at the normal frog neuromuscular junction, and is tightly associated with the terminal Schwann cell. Blocking presynaptic activity via denervation, or TTX nerve blockade, results in a decreased level of active MMP3 at the neuromuscular junction. The loss of active MMP3 at the neuromuscular junction in denervated muscles can result from decreased activation of pro-MMP3, or it could result from increased inhibition of MMP3. These results support the hypothesis that changes in synaptic activity can alter the level of active MMP3 at the neuromuscular junction.


Generation of baculovirus vectors for the high-throughput production of proteins in insect cells.
The baculovirus expression system is one of the most popular methods used for the production of recombinant proteins but has several complex steps which have proved inherently difficult to adapt to a multi-parallel process. We have developed a bacmid vector that does not require any form of selection pressure to separate recombinant virus from non-recombinant parental virus. The method relies on homologous recombination in insect cells between a transfer vector containing a gene to be expressed and a replication-deficient bacmid. The target gene replaces a bacterial replicon at the polyhedrin loci, simultaneously restoring a virus gene essential for replication. Therefore, only recombinant virus can replicate facilitating the rapid production of multiple recombinant viruses on automated platforms in a one-step procedure. Using this vector allowed us to automate the generation of multiple recombinant viruses with a robotic liquid handler and then rapidly screen infected insect cell supernatant for the presence of secreted proteins.


Programming balanced optical beam splitters in white paint.
Wavefront shaping allows for ultimate control of light propagation in multiple-scattering media by adaptive manipulation of incident waves. We shine two separate wavefront-shaped beams on a layer of dry white paint to create two enhanced output spots of equal intensity. We experimentally confirm by interference measurements that the output spots are almost correlated like the two outputs of an ideal balanced beam splitter. The observed deviations from the phase behavior of an ideal beam splitter are analyzed with a transmission matrix model. Our experiments demonstrate that wavefront shaping in multiple-scattering media can be used to approximate the functionality of linear optical devices with multiple inputs and outputs.


Oral and gastrointestinal manifestations of epidermolysis bullosa.
The mouth, oesophagus, and anus are often involved in dystrophic and junctional epidermolysis bullosa, but the frequency is unknown. Among 246 patients with epidermolysis bullosa, dysphagia developed in 76% of those with recessive dystrophic, in 20% of those with dominant dystrophic, in 15% of those with junctional, and in 2% of those with simplex forms. Lingual adhesions or microstomia occurred in dystrophic epidermolysis bullosa only, but were eight times more common in recessive than in dominant subtypes. These lesions are provoked by the trauma of eating and further reduce food intake, which exacerbates constipation caused by anal blisters and results in malnutrition. Management requires specialised multidisciplinary care.